Post mortem studies have shown that patients dying from severe SARS-CoV-2 infection frequently have pathological changes in their central nervous system, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized COVID-19 patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on magnetic resonance imaging (MRI) is inconclusive. We therefore used ultra-high field (7T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7T QSM data from 30 patients, scanned 93 – 548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients’ QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-Dimer and platelet levels), functional recovery (modified Rankin scale; mRS), depression (PHQ-9) and anxiety (GAD-7). In COVID-19 survivors the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. Using non-invasive ultra-high field 7T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors. This study contributes to understanding the mechanisms of long-term effects of COVID-19 and recovery.

Background/Objectives: Magnetisation Transfer (MT) MRI is used for neuro-degenerative disorders, including Multiple Sclerosis (MS), providing an indirect measure of large biomolecular MR signal sources which cannot be observed directly because their typical T2 is usually much shorter than the echo time (TE) of conventional MR sequences. We investigated a 3D-radial Zero Time of Echo (ZTE) MT-weighted sequence with potentially enhanced sensitivity to short-T2 MR signals indirectly (via MT weighting) and directly (due to the short TE). Methods: The sequence runs on a human 7T MR scanner, producing whole-brain MT-weighted images with isotropic 0.8 mm resolution in 6.5 minutes. One RF pulse is used to suppress the fat signal and generate MT weighting, reducing RF power deposition to moderate levels. The small excitation pulses and the “quasi-adiabatic” MT pulse mitigate the negative effects of inhomogeneous transmit RF fields observed at 7T in the human head, facilitating the generation of uniform Magnetisation Transfer Ratio (MTR) maps. Results: Results from a biologic phantom, a healthy volunteer, and an MS patient illustrate important imaging features of the “SilentMT” sequence. When the MS patient images were compared with Fluid Attenuated Inversion Recovery (FLAIR) images taken on the same patient at 1.5T and 7T, SilentMT was able to detect all the MS lesions observed on the “reference truth” 1.5T FLAIR; 7T FLAIR, however, failed to detect some lesions in the temporal lobe and brain stem. SilentMT detected a lesion which was not immediately apparent on either FLAIR image. Increased MTR was observed in some regions of the brain of the MS patient, notably the left temporal lobe. Conclusions: This initial investigation of an MT-weighted ZTE sequence shows evidence that it may be more sensitive to pathology in a patient with MS.